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Why Choose Immune Cells as Targets to Improve mRNA Vaccine Efficacy?
In the field of vaccine development, the emergence of mRNA-based vaccines has revolutionized traditional approaches, offering unparalleled potential in terms of safety, efficacy, and adaptability. These vaccines come with various advantages, including rapid development timelines, scalable production, and the ability to swiftly adapt to new pathogens. mRNA vaccines present an enticing pathway for combating infectious diseases, including those caused by newly emerging pathogens and drug-resistant bacteria. While mRNA vaccines hold immense promise, challenges persist, including transient antibody responses and off-target effects associated with systemic delivery. To address these limitations, targeting mRNA delivery to immune cells, particularly antigen-presenting cells (APCs), has emerged as a promising strategy. By directing mRNA to specific immune cell populations, such as dendritic cells (DCs), enhanced efficacy of mRNA vaccines can be achieved while minimizing side effects.
Figure 1. mRNA vaccine.
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Types of Immune Cells as Targets
The selection of target cells is critical for optimizing vaccine efficacy and immune response. Here are the various types of target cells involved in vaccine response, including dendritic cells (DCs), plasmacytoid dendritic cells (pDCs), follicular dendritic cells (FDCs), Langerhans cells (LCs), and macrophages. Each cell type plays a unique role in immune surveillance and response, providing unique advantages and challenges for vaccine delivery and immunotherapy.
Conventional Dendritic Cells (cDCs)
Conventional dendritic cells (cDCs) serve as key orchestrators of immune responses, bridging innate and adaptive immunity. They comprise two main subsets: cDC1 and cDC2, each with specialized functions and markers. cDC1s excel in cross-presentation of antigens to CD8+ T cells, promoting cytotoxic immune responses against intracellular pathogens. On the other hand, cDC2s predominantly drive CD4+ T cell responses, facilitating humoral immunity and Th1/Th2 differentiation. Targeting cDCs in vaccine formulations holds promise for eliciting robust and tailored immune responses against various pathogens.
Plasmacytoid Dendritic Cells (pDCs)
Plasmacytoid dendritic cells (pDCs) are pivotal players in antiviral immunity, characterized by their unique ability to detect nucleic acids and produce type I interferons (IFNs). Despite their relatively low efficiency in antigen presentation compared to cDCs, pDCs play a crucial role in initiating rapid and robust immune responses against viral infections. Targeting pDCs in vaccine design could enhance early immune activation and bolster the organism's ability to combat viral pathogens.
Follicular Dendritic Cells (FDCs)
Follicular dendritic cells (FDCs) are specialized subsets of DCs found in lymphoid tissues, particularly within germinal centers. They play a central role in facilitating B cell activation, affinity maturation, and the generation of long-lasting antibody responses. Targeting FDCs in vaccine formulations holds immense potential for optimizing humoral immunity and eliciting potent antibody-mediated immune responses against a myriad of pathogens.
Langerhans Cells (LCs)
Langerhans cells (LCs) are skin-resident immune sentinels that play a crucial role in initiating immune responses against cutaneous pathogens. Expressing the Langerin receptor, LCs possess unique capabilities in antigen sampling and immune activation within the skin microenvironment. Targeting LCs in skin immunization strategies could harness their localized immune-stimulatory properties, eliciting robust and site-specific immune responses against skin pathogens.
Macrophages
Macrophages serve as versatile immune cells with diverse functions in phagocytosis, antigen presentation, and cytokine secretion. While they exhibit limited antigen-presenting capacity compared to DCs, macrophages play a critical role in tissue remodeling and immune modulation. Targeting macrophages in vaccine delivery strategies, particularly for respiratory infections, could enhance localized immune responses and facilitate crosstalk between different immune cell populations.
Types of Receptors of Immune Cells
Types and degree of immune response depend on the environment in which antigens are captured, including the receptors used for internalization. Therefore, the success of targeted delivery platforms depends on the correct selection of ligand-receptor pairs.
C-Type Lectin Receptors (CLRs)
- General Characteristics of CLRs
CLRs constitute a superfamily of over 1,000 proteins, expressed abundantly on the surface of various immune cells (including DCs, macrophages, and neutrophils), and play roles in recognizing self and non-self antigens, internalization, antigen processing, initiating immune responses, and regulating intercellular interactions. They are targeted for antigen and mRNA delivery:
CLRs feature a conserved structural motif - carbohydrate recognition domain (CRD), which recognizes carbohydrate structures associated with pathogens (viruses, bacteria, and fungi) via interaction with conserved calcium-binding sites, facilitating recognition and phagocytosis. CLR signaling can be categorized into two groups: the first group transduces intracellular signals via activation of immunoreceptor tyrosine-based activation motifs (ITAM) (e.g., Clec-2, Dectin-1) or by binding with the ITAM-carrying FcRγ adaptor molecule (Dectin-2, Mincle, BDCA-2). Upon phosphorylation, ITAM motifs recruit and activate Syk, which induces transcription of pro-inflammatory cytokines by activating the NF-kB complex subunit. The second group of CLRs possesses immunoreceptor tyrosine-based inhibition motifs (ITIM) at their cytoplasmic termini (e.g., MICL).
- Mannose Receptors
Mannose receptors (CD206, MR) are internalization receptors expressed by macrophages and DCs, mediating cross-presentation of mannose glycans (from simple mannose to complex mannose polysaccharide structures) as well as alginates and sulfated LacdiNAc soluble ligands. These characteristics make mannose-based targeting one of the most common CLR targeting strategies. Numerous reports indicate that mannose-based strategies increase the internalization and transfection of mRNA vaccines in immune cells via receptor-mediated mechanisms.
- Other C-Type Lectins Receptors
| Other C-Type Lectins | Description |
| DC-SIGN | Calcium-dependent, present on human DCs and subsets of macrophages, can bind high mannose glycosylated glycoconjugates and antigens containing alginates, mediating DC-T cell interactions by promoting T cell adhesion to DC surfaces to search for peptide antigens. DC-SIGN induces intracellular signaling to regulate signal transduction of other pathogen recognition receptors (PRRs) such as TLRs. |
| DEC-205 (CD205) | Expressed on DCs, monocytes, and LCs, also expressed at low levels on B cells, T cells, and NK cells, involved in recognizing apoptotic and necrotic signals, mediating endocytosis, and enhancing MHC II presentation. Most DEC-205 targeting relies on the use of antibodies or antibody fragments, resulting in effective DC targeting and enhanced antigen cross-presentation. |
| Dectin-1 | Expressed by DCs, macrophages, monocytes, neutrophils, and subsets of T cells, specifically recognizes soluble and particulate β(1-3) and/or β(1-6)-glucans with varying affinities, promoting particle uptake via actin-dependent phagocytosis and participating in cell activation via ITAM-like motifs. Due to its ability to bind to CD4+ and CD8+ T cells and promote proliferation, it is considered a co-stimulatory molecule. |
| Langerin (CD207) | Expressed by LCs, dermal DCs, and other DC subsets, successful targeting of Langerin has been achieved in vitro using antibodies or small molecule glycans as targeting ligands. Schulze et al. selectively targeted nanoparticles (liposomes) to human LCs using a Langerin ligand, which can be used for functionalized delivery of drugs, antigens, or toxins to LCs. |
| DNGR-1 (Clec9a) and MGL (Clec10a) | DNGR-1/Clec9a is selectively expressed on human cDC1. Interaction with this receptor promotes humoral immunity in non-human primates, and recent studies have found that DNGR-1-specific peptides can target nanoparticles to Clec9a+ DCs. MGL is specifically expressed on human cDC2 (CD1c+ DCs), selectively binding to GalNAc-terminated and differently glycosylated peptides of MUC1. Heger et al. found that using a Clec10a-binding glycopeptide selectively targeted CD1c+ cells (cDC2) in PBMCs, although no activation or cytokine secretion of CD1c+ DCs was observed with the ligand alone. |
| hDCIR (Clec4a) | Expressed on CD14+ monocytes, CD15+ granulocytes, all DC subsets (including pDCs), and B cells in peripheral blood, not found in T cells. Targeting antigens to DCIR using antibodies increases cross-presentation in LCs, blood mDCs, and pDCs and enhances CD8+ T cell priming in vitro. |
Other Receptors for mRNA Targeted Delivery
Toll-like receptors (TLRs)
Expressed by cells of the innate immune system (such as macrophages and DCs) and subsets of adaptive immune cells, play a critical role in the innate immune system by recognizing pathogen-associated molecular patterns (PAMPs), and studies have used Pam3CSK4 (a TLR-2 agonist) as a targeting ligand to deliver nanoparticles to DCs.
X-C chemokine receptor 1 (XCR1)
Recognizes the chemokine XCL1, selectively expressed on cDC1. Fossum et al. studied Clec9a, DEC-205, and XCR-1 as targets, injecting DNA vaccines encoding antigen-fused single-chain variable fragments (scVf) into mice, and found that targeting XCR-1 enhanced IFN-γ+CD8+ T cell responses in the spleen and lungs, with stronger cytotoxicity. Although both Clec9a and XCR1 are cDC1-specific, they lead to different outcomes, indicating that not only cell subtype but also the receptor itself determines targeting outcomes and efficacy.
Prospects for the Development of Immune Cell-Targeted mRNA Vaccines
Targeting specific receptors on cells of the innate immune system can generate stronger and more durable immune responses tailored to vaccines. Combined targeting strategies of different subsets of innate immune cells are particularly promising because of their unique and central roles in the immune response. For instance, macrophages drive inflammatory responses, while dendritic cells play a crucial role in antigen presentation to T cells. Simultaneously targeting both cell types may contribute to initiating improved antigen-specific immune responses. Further research is needed to identify potential shared key receptors in different cell types or to formulate LNPs with combinations of multiple targeting ligands. In the development of RNA delivery vehicles, it is important to consider the compatibility of components in the formulation steps, as well as the necessity of maintaining effective endosomal escape and sufficient presentation of multivalent ligands.
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